US 2012005 8208A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0058208A1 Jacob (43) Pub. Date: Mar. 8, 2012

(54) SYNERGISTIC COMPOSITION FOR Publication Classification ENHANCING BOAVAILABILITY OF (51) Int. Cl. A636/906 (2006.01) (75) Inventor: Sinnakattu Varkey Jacob, Kochi 3. 46 308: (IN) A636/898 (2006.01) (73) Assignee: SYNTHITE INDUSTRIES LTD., (52) U.S. Cl...... 424/756; 424/725; 514f627 Kochi (IN) (57) ABSTRACT (21) Appl. No.: 13/083,388 The present disclosure relates to a composition to enhance the bioavailability of curcumin. In one embodiment, a composi (22) Filed: Apr. 8, 2011 tion comprising plant extracts of curcumin, and gin ger, wherein the extracts of and Vanilla are rich in (30) Foreign Application Priority Data gingerol and respectively, is provided. In other embodiments, curcumin, and one or more items selected from Sep. 4, 2010 (IN) ...... 999/CHFA2010 the group of Vanilla, ginger and is provided.

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SYNERGISTC COMPOSITION FOR had higher MMSE results than those who did not 13. From ENHANCING BOAVAILABILITY OF a scientific standpoint, though, this does not show whether the CURCUMIN curry caused it, or people who had healthy habits also tended to eat the curry, or some completely different relationship. CROSS-REFERENCE TO RELATED 0010 Numerous studies have demonstrated that cur APPLICATION , amongst only a few other things such as high impact 0001. This application claims priority to and the benefit of exercise, learning, bright light, and antidepressant usage, has Indian Provisional Patent Application number 999/CHF/ a positive effect on neurogenesis in the hippocampus and 2010, entitled “A Synergistic Composition for Enhancing concentrations of brain-derived neurotrophic factor (BDNF), Bioavailability of Curcumin, filed Apr. 9, 2010, the contents reductions in both of which are associated with stress, depres of which are hereby incorporated by reference into the present sion, and anxiety 1415 16. Curcumin has also been application. demonstrated to be a selective monoamine oxidase inhibitor (MAOI) of type MAO-A. BACKGROUND 0011. In 2009, an Iranian group demonstrated the combi nation effect of curcumin with 24 antibiotics against Staphy 0002 1. Technical Field lococcus aureus. It was shown that in the presence of a Sub 0003. The present disclosure relates generally to a com inhibitory concentration of curcumin, the antibacterial position and related methods for providing health benefits, activities of cefixime, cefotaxime, Vancomycin and tetracy and, more particularly, to compositions and related methods cline increased against test strain 17. Curcumin's potential of ginger and Vanilla extract with curcumin to increase the anticancer effects stem from its ability to induce in bioavailability of curcumin and inhibiting tumor growth. cancer cells without cytotoxic effects on healthy cells. Cur 0004 2. Description of Related Art cumin can interfere with the activity of the transcription fac 0005 Research in the latter half of the 20th century has tor NF-KB, which has been linked to a number of inflamma identified that curcumin has a wide range of potential thera tory diseases such as cancer 18. peutic and preventive effects. So far, these effects have not 0012. A 2009 study suggested that curcumin may inhibit been confirmed in humans. However, as of 2008, numerous mTOR complex I via a novel mechanism (19. Another 2009 clinical trials inhumans were underway, studying the effect of study on curcumin effects on cancer Stated that curcumim curcuminon numerous diseases including multiple myeloma, "modulates growth of tumor cells through regulation of mul , myelodysplastic Syndromes, colon cancer, tiple cell signaling pathways including cell proliferation path psoriasis, and Alzheimer's disease 1. way (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl 0006. In vitro and animal studies have suggested the cur XL, cFLIP. XIAP. c-IAP1), caspase activation pathway cumin may have antitumor 23, antioxidant, anti-arthritic, (caspase-8.3.9), tumor Suppressor pathway (p53, p21) death anti-amyloid, anti-ischemic 4, and anti-inflammatory prop receptor pathway (DR4, DR5), mitochondrial pathways, and erties 5. Anti-inflammatory properties may be due to inhi protein kinase pathway (JNK, Akt, and AMPK) 20. When bition of eicosanoid biosynthesis 6. In addition, curcumin 0.2% curcumin was added to a diet given to rats or mice may be effective in treating malaria, preventing cervical can previously given a carcinogen, it significantly reduced colon cer, and may interfere with the replication of the HIV virus carcinogenesis. 7. In HIV, curcumin appears to act by interfering with the 0013 The pharmacological safety and efficacy of cur P300/CREB-binding protein (CBP). It is also hepatoprotec cumin makes it a potential compound for the treatment and tive 8. prevention of a wide variety of human diseases. In spite of its 0007. A 2008 study at Michigan State University showed efficacy and safety, curcumin has not yet been approved as a that low concentrations of curcumin interfere with Herpes therapeutic agent, and the relative bioavailability of curcumin Simplex Virus-1 (HSV-1) replication 9. The same study has been highlighted as a major problem for this. Major showed that curcumin inhibited the recruitment of RNA poly reasons contributing to the low plasma and tissue levels of merase II to viral DNA, thus inhibiting the transcription of the curcuminappear to be due to poor absorption, rapid metabo viral DNA. This effect was shown to be independent of the lism, and rapid systemic elimination. The low serum level of effect on the histone acetyltransferase activities of p300/CBP. curcuminis one of the major factors affecting its bioavailabil A 1999 University of Cincinnati study indicated that cur ity. A recent study showed that after oral administration of cumin is significantly associated with protection from infec 400 mg of curcumin to rats, only traces of unchanged drug tion by HSV-2 in animal models of intravaginal infections were found in the liver and kidney. At 30 min, 90% of cur 10. cumin was found in the stomach and Small intestine, but only 0008 Curcumin acts as a free scavenger and anti 1% was present at 24 hours. Once absorbed, curcumin is oxidant, inhibiting lipid peroxidation 11 and oxidative DNA metabolized rapidly in the liver and excreted out of the bio damage. Curcuminoids induce S-transferase and logical system. This seriously limits the ability of curcuminto are potent inhibitors of cytochrome P450. A 2004 UCLA reach targets distant from the gut and exert its beneficial Veterans Affairs study involving genetically altered mice Sug action. gested that curcumin might inhibit the accumulation of 0014) To improve the bioavailability of curcumin, numer destructive beta-amyloid in the brains of Alzheimer's disease ous approaches have been undertaken. The reports So far patients and also break up existing plaques associated with show that the absorption, biodistribution, metabolism and the disease 12. elimination of curcuminare the major problems that affect the 0009. There is also circumstantial evidence that curcumin bioavailaibility of curcumin. Several strategies has been tried improves mental functions. A survey of 1,010 Asians who ate to overcome these problems. The use of adjuvants (bioavail yellow curry and were between the ages of 60 and 93 showed ability enhancers) is one important means in this route. Other that those who ate the sauce “once every six months' or more methods include nanoparticle technology, encapsulation of US 2012/00582O8 A1 Mar. 8, 2012

curcumin in liposome, complexation of curcumin to form (0023 6. Srivastava, K C: Bordia A. Verma S K (April micelles and phospholipids, and the introduction of biocon 1995). “Curcumin, a major component of the food spice jugates. (Curcuna longa), inhibits aggregation and alters 00.15 Adjuvants are compounds that are concomitantly eicosanoid metabolism in human blood platelets'. Pros administered with the drug/nutraceutical so as to enhance the taglandins Leukot Essent Fatty Acids 52 (4): 223-7. bioavailability of the latter. One of the main reasons for the poor bioavailability of curcumin is glucuronidation in the (0024 7. Padma, TV (2005-03-11). “Turmeric can combat liver. The adjuvants like are shown to inhibit this malaria, cancer virus and HIV. SciDev.net. metabolic pathway of glucuronidation, thus increasing the (0025 8. Marotta, F.; et al. (October 2003). “Hepatopro bioavailability of curcumin. There are several reports of other tective effect of a curcumin/absinthium compound in adjuvants that show synergetic effects when used in combi experimental severe liver injury'. Chinese Journal of nation with curcumin. Digestive Diseases (Blackwell Publishing) 4(3): 122-7. 0016 Several adjuvants are reported to enhance the bio (0026 9. Kutluay S B, Doroghazi J, Roemer ME, Triezen availability of curcumin. Concomitant administration of pip berg SJ (January 2008). “Curcumin inhibits herpes sim erine along with curcumin (Bioperin) has been shown to plex virus immediate-early gene expression by a mecha increase the bioavailability of curcumin. Piperine inhibits nism independent of p300/CBP histone acetyltransferase hepatic and intestinal glucuronidation, which is the major activity”. Virology 373 (2): 239. pathway of curcumin metabolism, thereby reducing glucu ronidation of curcumin, and Subsequently reducing the elimi (0027 10. Bourne KZ, Bourne N, Reising SF, Stanberry L. nation from the body. The human body uses glucuronidation R (1999 July). “Plant products as topical microbicide can to make a large variety of substances more water-soluble, and, didates: assessment of in vitro and in vivo activity against in this way, allows for their subsequent elimination from the herpes simplex virus type 2. Antiviral research 42 (3): body upon urination. 219-26. 0017 Gingerol has also been reported to enhance the bio 0028 11. Shukla PK Khanna VK. Khan MY. Srimal RC. availability of curcumin. In a patent work by Khajuria et el “Protective effect of curcumin against lead neurotoxicity in (2003), it was shown that gingerol enhances the bioavailabil rat'. Hum Exp Toxicol. 2003 December; 22(12):653-8. ity of several nutraceutical drugs such as vitamins A. E. C. (0029 12. Yang, F: Lim G. P. Begum A N: Ubeda O J: Folic acid, b-carotene, silymarin, isoleucine, Zinc and potas Simmons MR; Ambegaokar S S; Chen PP; Kayed R: sium. The patent shows a detailed study of gingerol use as a Glabe CG: Frautschy SA; Cole G M (February 2005). bioavailability enhancer. A comparison of the activity of gin “Curcumin inhibits formation of amyloid beta oligomers gerol to piperine and a combination of (50:50) gingerol: pip and fibrils, binds plaques, and reduces amyloid in Vivo”. erine is also reported. For the given dose (50 mg/kg) gingerol Journal of Biological Chemistry (American Society for was shown to enhance the bioavailability of curcumin by 43% Biochemistry and Molecular Biology) 280 (7): 5892-901. whereas piperine showed the same enhancement by 33%. A combination of gingerol and piperin showed a curcumin 0030 13. Ng T P; Chiam PC; Lee T: Chua HC: Lim L: bioenhancement of 70%. The screening and comparison has Kua E H (November 2006). “Curry consumption and cog been made for several immunosuppresents, herbal formula nitive function in the elderly'. American Journal of Epide tions, cortisosteroids, anti-histamines and anti-ulcer drugs, miology (Oxford University Press) 164 (9): 898-906. which shows gingerol has a higher bioenhancing activity 0031 14. Xu Y. Ku B, Cui L, Li X, Barish PA, Foster TC, when compared to piperine. Other reported bioavailability Ogle W. O. (August 2007). “Curcumin reverses impaired enhancers of curcumin are , EGCG, quarecetin and hippocampal neurogenesis and increases serotonin recep genisetein. The activity of these adjuvants is not as effective tor 1A mRNA and brain-derived neurotrophic factor as that of piperine and gingerol. expression in chronically stressed rats'. Brain Res 1162:9. 0032) 15. Wu A, Ying Z, Gomez-Pinilla F. (February REFERENCES 2006). “Dietary curcumin counteracts the outcome of trau 0018 1. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV matic brain injury on oxidative stress, synaptic plasticity, (June 2008). “Curcumin: from ancient medicine to current and cognition’. Experimental Neurology 197 (2): 309. clinical trials”. Cell. Mol. Life. Sci. 65 (11): 1631-52. 0033 16. Bala K, Tripathy BC, Sharma D. (April 2006). 0019 2. Aggarwal, B B.: Shishodia S. (May 2006). “Neuroprotective and anti-ageing effects of curcumin in “Molecular targets of dietary agents for prevention and aged rat brain regions'. Biogerontology 7 (2): 81. therapy of cancer. Biochemical Pharmacology (Elsevier) 0034 17. Kamyar Mollazadeh Moghaddam, Mehrdad 71 (10): 1397-421. Iranshahi, Mahsa Chitsazian Yazdi, Ahmad Reza Shah 0020 3. Choi, Hyunsung; et al. (July 2006). “Curcumin verdi (August 2009). “The combination effect of curcumin Inhibits Hypoxia-Inducible Factor-1 by Degrading Aryl with different antibiotics against Staphylococcus aureus'. Hydrocarbon Receptor Nuclear Translocator: A Mecha IJGP3(2):141-143. nism of Tumor Growth Inhibition'. Molecular Pharmacol 0035. 18. Aggarwal BB, Shishodia S. “Suppression of the ogy (American Society for Pharmacology and Experimen nuclear factor-kappaB activation pathway by spice-derived tal Therapeutics) 70 (5): 1664-71. : reasoning for seasoning. Ann NYAcad. 0021. 4. Shukla PK Khanna V K, Ali M. M. Khan M. Y. Sci. 2004 December; 1030:434-41. Srimal R. C. “Anti-ischemic effect of curcumin in rat 0036) 19. Beevers CS, Chen L. Liu L, Luo Y. Webster NJ, brain”, Neurochem Res. 2008 June; 33(6):1036-43. Huang S (February 2009). “Curcumin disrupts the Mam 0022. 5. Stix, Gary (February 2007). “Spice Healer”. Sci malian target of rapamycin-raptor complex”. Cancer Res. entific American. 69 (3): 1000-8. US 2012/00582O8 A1 Mar. 8, 2012

0037. 20. Ravindran, J.; Prasad, S.; Aggarwal, B. (July plasticizers, preservatives, Suspending agents, emulsifying 2009). “Curcuminand Cancer Cells: How Many Ways Can agents and spheronization agents. Curry Kill Tumor Cells Selectively?”. The AAPS journal 0046. In yet another aspect of at least one embodiment of 11 (3): 495. the present disclosure, the composition is formulated into dosage forms selected from a group consisting of tablets, SUMMARY troches, lozenges, aqueous or oily Suspensions, capsule, emulsion, creams, sprays, drops, dispersible powders or gran 0038. In one embodiment of the present disclosure, a syn ules, syrups, elixirs, phytoceuticals, nutraceuticals and food ergistic composition for enhancing the bioavailability of cur stuffs. cumin, containing curcumin, Vanilla extract and ginger 0047. In yet another embodiment of the present disclo extract, optionally along with pharmaceutically acceptable Sure, a process is disclosed for the preparation of a synergistic excipients is provided and a related method of providing composition for enhancing the bioavailability of curcumin bioaviable curcumin is also provided. In another embodiment containing curcumin, Vanilla extract and ginger extract of the present disclosure, a process for preparation of a syn including, but not limited to, mixing the curcumin, the Vanilla ergistic composition for enhancing the bioavailability of cur extract and the ginger extract to obtain a mixture, blending the cumin containing curcumin, Vanilla extract and ginger extract mixture, and optionally adding excipients to obtain the Syn comprising acts of mixing the curcumin, Vanilla extract and ergistic composition. ginger extract to obtain a mixture, blending the mixture, and 0048. In yet another aspect of at least one embodiment of optionally adding excipients to obtain the Synergistic compo the present disclosure, the curcumin, Vanilla extract and gin sition is provided. In yet another embodiment of the present ger extract are in powder form. disclosure, a method of enhancing the bioavailability of cur 0049. In yet another aspect of at least one embodiment of cumin, the method including administering biologically Suit the present disclosure, the blending is carried out using a able amounts of a synergistic composition including cur blender selected from a group consisting of a ball mill mixer, cumin, Vanilla extract and ginger extract, optionally along sand mill mixer, multi mill mixer, pulverizer, and granulator. with pharmaceutically acceptable excipients to a subject in 0050. In yet another embodiment of the present disclo need thereof, is provided. sure, a method is disclosed of enhancing the bioavailability of 0039. In yet another embodiment of the present disclo curcumin. In an aspect of at least one embodiment, the Sure, a synergistic composition for enhancing the bioavail method involves administering biologically suitable amounts ability of curcumin, containing curcumin, Vanilla extract and of a Synergistic composition comprising curcumin, Vanilla ginger extract, optionally along with pharmaceutically extract and ginger extract, optionally along with pharmaceu acceptable excipients, is provided. tically acceptable excipients to a subject in need thereof. 0040. In yet another embodiment of the present disclo 0051. In another aspect of at least one embodiment of the Sure, a synergistic composition for enhancing the bioavail present disclosure, the Subject is a mammal. In another aspect ability of curcumin, containing curcumin and Vanilla extract of at least one embodiment, the Subject is a human. and/or capsaicin optionally along with pharmaceutically 0.052 One embodiment of the present disclosure provides acceptable excipients, is provided use of a combination of ginger extract rich in gingerol (up to 0041. In an aspect of at least one embodiment of the 35% purity) and vanilla extract rich in vanillin (up to 5% present disclosure, curcumin is present in a range from about purity) that enhances the bioavailability of curcumin. It was 60% weight/weight to about 85% weight/weight, ginger found that when a composition (composition 1) containing extract is present in a range from about 5% weight/weight to ginger extract rich in gingerol (10%) and Vanilla extract about 25% weight/weight, and the vanilla extract is present in (0.75% rich in vanillin) with curcumin (94% curcuminoids) is a range from about 0.5% weight/weight to about 5% weight/ administered orally to Sprague dawley rats, the concentration weight. of curcumin in blood plasma had a significant increase when 0042. In another aspect of at least one embodiment of the compared to the control. The enhancement in bioavailability present disclosure, curcumin is present in a range of about is found to be about 7.5 folds when compared to the control. 84% w/w to about 86% w/w, ginger extract is present in a There is an enhancement in the bioavailability of the cur range of about 12% w/w to about 13% w/w and vanilla extract cumin when the composition is used as compared to the is present in a range of about 2% w/w to about 3% w/w bioavailability of curcumin when used with ginger extract 0043. In another aspect of at least one embodiment of the and/or vanilla extract perse. present disclosure, curcumin contains curcuminoids in a 0053 Apart from enhancing the bioavailability of cur range of about 92% to a range of about 94%, ginger extract cumin with the help of the extract, the composition smells contains gingerol in a range of about 10% to a range of about pleasant due to the presence of Vanillin. 12% and Vanilla extract contains Vanillin in a range of about 0054. In yet another embodiment of the present disclo 0.5% to a range of about 2.5%. Sure, the synergistic composition of the present disclosure is 0044. In yet another aspect of at least one embodiment of also noted for enhancing anti-cancer activity by inhibiting the present disclosure, the curcumin, Vanillin and gingerol tumor growth. can be obtained from one or more plants and by chemical 0055. In yet another embodiment of the present disclo synthesis. Sure, a method of reducing the size of one or more tumors in 0045. In yet another aspect of at least one embodiment of a mammal is provided. The method comprises administering the present disclosure, the excipients are selected from a to a mammal having a tumor a composition containing an group consisting of granulating agents, binding agents, lubri effective amount of curcumin and an effective amount of cating agents, disintegrating agents, Sweetening agents, ginger extract and an effective amount of Vanilla extract. glidants, anti-adherents, anti-static agents, Surfactants, anti 0056. These, as well as other components, steps, features, oxidants, coating agents, coloring agents, flavoring agents, objects, benefits, and advantages, will now become clear from US 2012/00582O8 A1 Mar. 8, 2012

a review of the following detailed description of illustrative The vanilla extract obtained is mixed with maltodextrin and embodiments, the accompanying drawings, and the claims spray-dried to a powder product with 0.75% vanillin content. Hereafter, vanilla extract is defined as the vanilla plant extract BRIEF DESCRIPTION OF DRAWINGS mixed with maltodextrin, in the powder form with a vanillin content of 0.75%. 0057 The drawings disclose illustrative embodiments. 0067. In an embodiment of the present disclosure, com They do not set forth all embodiments. Other embodiments mercially available curcumin, ginger extract and Vanilla may be used in addition or instead. Details that may be appar extract with appropriate activity can also be used. ent or unnecessary may be omitted to save space or for more 0068 Composition 1 effective illustration. Conversely, some embodiments may be 0069. 42.5 grams of curcumin are mixed with 6.25 grams practiced without all of the details that are disclosed. When of ginger extract and 1.25 grams of vanilla extract in a mortar the same numeral appears in different drawings, it is intended and mixed in a lab homogenizer to equal 50 grams of Com to refer to the same or like components or steps. position 1. 0058 FIG. 1 is a graph showing the results of oral phar 0070 This formulation is also prepared on a large scale in macokinetics studies in male Sprague Dawley rats (1 g/Kg the plant level. For example, 85 kilgrams of curcumin extract body weight) demonstrating some of the benefits and advan are blended along with 12.5 kilograms of ginger extract and tages of the present disclosure. 2.5 kilograms of vanilla extractina homogenizer to equal 100 0059 FIG. 2 is a graph showing in vivo anti-cancer activ kilograms of Composition 1. ity of curcumin composition 1 in an HCT-116 human (0071 Composition 2 Xenograft model. 0072 42.5 grams of curcuminare mixed with 7.5 grams of ginger extract in a mortar and mixed in a lab homogenizer to DETAILED DESCRIPTION OF ILLUSTRATIVE equal 50 grams of Composition 2. EMBODIMENTS (0073 Composition 3 0060 Illustrative embodiments are now discussed. Other 0074 44.5 grams of curcumin are mixed with 4.25 grams embodiments may be used in addition or instead. Details that of ginger extract and 1.25 grams of vanilla extract in a mortar may be apparentorunnecessary may be omitted to save space and mixed in a lab homogenizer to equal 50 grams of Com or for a more effective presentation. Conversely, some position 3. embodiments may be practiced without all of the details that (0075 Composition 4 are disclosed. 0076 46.5 grams of curcumin are mixed with 2.25 grams 0061 The details of a method of preparing the composi of ginger extract and 1.25 grams of vanilla extract in a mortar tion are given below. However, it should not be construed that and mixed in a lab homogenizer to equal 50 grams of Com the scope disclosure is limited to the examples. position 4. 0062 Experiment I: Preparation of Compositions (0077 Composition 5 0063. Materials Used to Prepare Compositions 0078 43.25 grams of curcuminare mixed with 6.25 grams 0.064 Curcumin: the turmuric extract with total curcumi of ginger extract and 0.5 gram of Vanilla extract in a mortar noids of 80-94%. Curcumin powder is extracted from tur and mixed in a lab homogenizer to equal 50 grams of Com meric (Curcuna longa) using ethyl acetate as a position 5. solvent. The extracted is refluxed with a non-polar (0079 Composition 6 Solvent (hexane) for removing the oil content present in the 0080 49 grams of curcumin are mixed with one gram of curcumin extract. Crystallizing from a suitable mixture of Vanilla extract in a mortar and mixed in a lab homogenizer to ethyl acetate and hexane results in further purification. The equal 50 grams of Composition 6. final crystallization is done using a suitable alcohol like iso I0081 Composition 7 proplyl, isobutyl, or neopentyl alcohol to get the total cur I0082 49.5 grams of curcuminare mixed with 0.5 gram of cuminoids to 94% Curcumin, demethoxycurcumin (DMC) high pure capsaicin in a mortar and mixed in a lab homog and bisdemethoxycurcumin (BDMC). Hereafter, curcumin enizer to equal 50 grams of Composition 7. is defined as the turmeric extract with total curcuminoids of I0083 Table I Compositions screened for oral pharma 92-94%. cokinetics studies 0065 Ginger extract: the ginger extract rich in gingerol. 0084 Curcumin Ginger raw material (RM) of the Burma variety is used for 0085 Control supercritical fluid extraction using CO (SCF CO) after Curcumin 85%+Ginger Extract 12.5%+Vanilla extract sun drying. The RM is loaded into the extractor where the 2.5% Composition 1 extraction is done for three hours at a bar pressure of 250 and 45°C. The top note is collected in the separator and gingerol Curcumin 85%+Ginger Extract 15% Composition 2 rich ginger extract is collected separately. The ginger extract Curcumin 89%+Ginger extract 8.5%+Vanilla extract is centrifuged to remove any moisture content that is in resin 2.5% Composition 3 form, having a gingerol content of 35%. The ginger extract is mixed with maltodextrin and spray-dried to get a powdered Curcumin 93%+Ginger extract 4.5%+Vanilla extract product with a gingerol content of 10% to 12%. Hereafter, 2.5% Composition 4 ginger extract is defined as the ginger extract mixed with Curcumin 86.5%+Ginger extract 12.5%+Vanilla maltodextrin, in the powder form with a gingerol content of extract 1% Composition 5 10-12%. 0066 Vanilla extract: the plant extract obtained from Curcumin 98%+Vanilla extract 2% Composition 6 grade A vanilla beans (RM) from Karnataka. The RM (having a moisture content of 30%) is extracted in aqueous alcohol. Curcumin 99%+Capsaicin 1% Composition 7 US 2012/00582O8 A1 Mar. 8, 2012

TABLE II The actual content of active ingredients in compositions by HPLC Composition

Ingredient Control 1 2 3 4 5 7

Curcuminoids 9% 94 80 79.9 83.69 85 81.45 92.3 93.06 Gingerol % 1.5 5.3 0.77 O.51 1.45 Vanillin 96 O.04 O.043 O.O21 O.OO9 O.O3S Capsaicin 96 1.1

0086 Formulation (0091 Bioanalytical Procedure 0087 Composition 1 is filled as such into capsules (500 0092 Curcumin in plasma samples quantified using UFLC with suitable extraction and recovery methods. mg each) for oral consumption. In another embodiment of the (0093. Data Analysis and Report present disclosure, the compositions are also obtained by 0094. The data was analyzed by WinNonlin (Pharsight) to mixing appropriate quantities of synthetic curcuminoids, gin calculate PK parameters: co, AUCo., C. T. t1/2 gerol and Vanillin. and MRT. The data is summarized in Table III.

TABLE III Curcumin compositions: Oral pharmacokinetics studies in male Sprague dawley rats (1 g/kg body weight equivalent dose) Mean Plasma PK Parameters

Curcumin Curcumin Curcumin 85% - (89%) + (93%) + Curcumin Ginger Ginger Ginger (86.5%) + extract Curcumin extract extract Ginger Curcumin (12.5%) + (85%) + (8.5%) + (4.5%) + extract (98%) + Curcumin Vaniilia Ginger Vaniilia Vaniilia (12.5%) + Vaniilia (99%) + extarct extarct extract extract Vaniilia extarct capsaicin Parameters Curcumin (2.5%) 15% (2.5%) (2.5%) extract (1%) (2%) (1%) Composition Control 1 2 3 4 5 6 7 number Route of Oral Oral Oral Oral Oral Oral Oral Oral administration Dose (g/kg) 1 1 1 1 1 1 1 1 equivalent dose Cmax (ng/mL) 127 290 290 167 143 216 152 149 Tmax (h) O.O8 1 O.O8 2 1 1.2 2 O.S AUClast 146 1104 566 581 321 423 615 498 (h * ng/mL) (O to 24 h) AUCinf 278 1372 856 818 367 450 909 966 (h * ng/mL) T/2. (h) 1.8 2.1 3.4 5.2 1.9 1.4 4.9 7.6 MRT last (h) O.83 2.8 2.29 3 2.2 2.1 3.3 3.2

0088 Experiment II: 0.095 Results 0089 Researchers used Sprague Dawley rats aged 7 to 8 0096. From the studies above, including but not limited to weeks and weighing around 200 to 250 grams. Animals fasted the results of the studies shown in Table III, it is evident that overnight with free access to water. The rats were given the the presence of ginger extract, Vanilla extract and capsaicin test Substance orally with a curcuminoids equivalent dose of enhances the plasma exposure of curcumin. 1 g/kg body weight (in a Suitable formulation and dose Vol 0097. As compared to the curcumin control, the composi ume). Blood samples (150-200 ml) were collected at various tion of curcumin (85%)+ginger extract (12.5%)+vanilla time points during the next 24 hours (0.08, 0.25, 0.5, 1, 2, 4, extract (2.5%) (Composition 1) resulted in a 7.5-fold increase 8 and 24 hours). in area under the curve (AUC) and a 2.3 fold increase in 0090 The blood samples were centrifuged at 3000 grams C, as detailed in FIG. 1. for five minutes at 4° C. and the corresponding plasma 0098. As compared to curcumin (85%)+ginger extract samples were harvested in clean, pre-labeled tubes. Analysis (15%) (Composition 2), the composition of curcumin (85%)+ by ultra-fast liquid chromatography (UFLC) was carried out ginger extract (12.5%)+vanilla extract (2.5%) (Composition on same day, or samples were stored at -80°C. until analysis 1) resulted in a two-fold increase in area under the curve was performed. (AUC). US 2012/00582O8 A1 Mar. 8, 2012

0099 Curcumin-i-Vanilla extract (Composition 6) and cur promising results for anti-cancer activity. The formulation at cumin--capsaicin (Composition 7) also showed increased 500 mg/kg dose resulted in a 36% inhibition in tumor growth, bioavailability as compared to curcumin control. compared to 27% with the curcumin control after 28 days of 0100. It should be appreciated that compositions contain treatment. No significant change was observed in their body ing one or more items selected from the group consisting of weight after 28 days of treatment. FIG. 2 provides the details Vanilla extract, capsaicin and ginger extract combined with of the analysis explained above. and curcumin worked synergistically to provide increased bioavailability that was statistically significant and far more 0105 While various aspects and embodiments have been than the sum of the bioavailability provided by the sum of the disclosed herein, other aspects and embodiments will be various component parts. apparent to those skilled in the art. The various aspects and 0101 Experiment III: Anti-Cancer Activity of Curcumin embodiments disclosed herein are for purposes of illustration Composition 1 and are not intended to be limiting, with the true scope and 0102 Human colorectal (HCT-116) xenograft model in spirit being indicated by the following claims. SCID mice 0106 The components, steps, features, objects, benefits 0103 Five-week-old female mice purchased from the and advantages that have been discussed are merely illustra Advanced Centre for Treatment, Research and Education in tive. None of them, nor the discussions relating to them, are Cancer (ACTREC) were used for in vivo experiments. The intended to limit the scope of protection in any way. Numer Institutional Animal Ethics Committee (IAEC) approved the ous other embodiments are also contemplated. These include in vivo study. Animals were injected with 1x10' HCT-116 embodiments that have fewer, additional, and/or different cells Subcutaneously in the flank region. Animals were moni components, steps, features, objects, benefits and advantages. tored daily during the period between inoculation and pal These also include embodiments in which the components pable tumor growth. Tumor size was measured with a digital and/or steps are arranged and/or ordered differently. Vernier caliper and tumor-bearing mice were randomized into control and treatment groups (n=8), when the tumor 0.107 Unless otherwise stated, all measurements, values, volume was attained ~100 mm. The tumor-bearing mice ratings, positions, magnitudes, sizes, and other specifications were orally administered with the curcumin Composition 1, that are set forth in this specification, including in the claims curcumin control and reference compound (Vorinostat) at the that follow, are approximate, not exact. They are intended to doses mentioned once daily for 28 days. Tumor Volume and have areasonable range that is consistent with the functions to was body weight was measured twice weekly. The following which they relate and with what is customary in the art to formula was used to calculate the tumor volume: Tumor vol which they pertain. ume=(lengthxwidth)/2. Percent reduction in tumor growth 0108) Nothing that has been stated or illustrated is was calculated with respect to the Vehicle treated group. intended or should be interpreted to cause a dedication of any

TABLE 4 In vivo anti-cancer activity of curcumin Composition 1 in HCT-116 human Xenograft model Tumor volume (mm), Mean, + SE Group Day 0 Day 4 Day 8 Day 12 Day 16

Control 137.9 25.9 235.0 - 49.2 436.5 97.8 595.9 115.2 768.8 140.0 (Vehicle) Vorinostat, 1316. 23.1 236.6 42.7 334.4 52.3 460.6 - 76.O 544.679.1 150 mg/kg Curcumin 132.3 - 23.3 287.752.3 405.9 64.O 619.5 73.2 861.8 147.1 control 500 mg/kg Curcumin 136.2 24.1 2434 35.1 362.3 46.3 516.9 64.3 737.3 98.2 Composition 1, 500 mg/kg

% Group Day 19 Day 22 Day 26 Day 29 Redn.

Control 1144.7 186.3 1102.3 1945 1445.5 - 272.2 1733.4 325.0 (Vehicle) Vorinostat, 6696 - 107.0 726.O. 120.8 916.6 157.9 979.1 - 157.2 47 150 mg/kg Curcumin 977.4 162.7 1052.1215.O. 1147.1 245.O. 1290.2 242.2 27 control 500 mg/kg Curcumin 832.5 103.1 890.4 117.4 10218 157.5 1161.3 214.6 36 Composition 1, 500 mg/kg

0104. It can be noted that the curcumin Composition 1 component, step, feature, object, benefit, advantage, or evaluated for in vivo anti-cancer activity in an HCT-116 equivalent to the public, regardless of whether it is recited in xenograft model of in SCID mice showed the claims. US 2012/00582O8 A1 Mar. 8, 2012

0109 The scope of protection is limited solely by the binding agents, lubricating agents, disintegrating agents, claims that now follow. That scope is intended and should be Sweetening agents, glidants, anti-adherents, anti-static interpreted to be as broad as is consistent with the ordinary agents, Surfactants, antioxidants, coating agents, coloring meaning of the language that is used in the claims when agents, flavoring agents, plasticizers, preservatives, Suspend interpreted in light of this specification and the prosecution ing agents, emulsifying agents and spheronization agents. history that follows and to encompass all structural and func 15. The composition in claim 1, wherein the composition is tional equivalents. formulated into dosage forms selected from a group consist 1. A composition for providing bioavailable curcumin, the ing of tablets, troches, lozenges, aqueous or oily Suspensions, composition comprising: capsules, emulsions, creams, sprays, drops, dispersible pow an effective amount of curcumin; ders or granules, syrups, elixirs, phytoceuticals, nutraceuti an effective amount of ginger extract; and cals and food stuffs. an effective amount of vanilla extract. 16. A method of providing bioavailable curcumin to a 2. The composition of claim 1, wherein the effective mammal, the method comprising: amount of curcumin is from about 60% weight/weight to administering to a mammal in need thereof a composition about 85% weight/weight. comprising curcumin, and one or more items selected 3. The composition of claim 1, wherein the effective from the group consisting of Vanilla extract, ginger amount of ginger extract is from about 5% weight/weight to extract and capsaicin. about 25% weight/weight. 17. The method of claim 16, further comprising adminis 4. The composition of claim 1, wherein the effective tering pharmaceutically acceptable excipients to the mam amount of vanilla extract is from about 0.5% weight/weight to mal. about 5% weight/weight. 18. A composition for providing bioavailable curcumin, 5. The composition of claim 1, wherein the effective the composition comprising: amount of Curcumin is about 84% w/w to about 86% w/w. 6. The composition as in claim 1 wherein the effective an effective amount of curcumin, and one or more selected amount of Ginger extract is about 12% w/w to about 13% w/w from ginger extract, Vanilla extract and capsaicin. 7. The composition as in claim 1 wherein the effective 19. The composition of claim 1, wherein the effective amount of Vanilla extract is about 2% w/w to about 3% w/w. amount of curcumin is comprised of curcuminoids of about 8. The composition of claim 1, wherein the effective 92% to a range of about 94%. amount of curcumin is comprised of curcuminoids of about 20. The composition of claim 1, wherein the effective 92% to a range of about 94%. amount of ginger extract is gingerol in a range of about 10% 9. The composition of claim 1, wherein the effective to a range of about 12%. amount of ginger extract is gingerol in a range of about 10% 21. The composition of claim 1, wherein the effective to a range of about 12%. amount of Vanilla extract is 0.5% to 2.5%. 10. The composition of claim 1, wherein the effective 22. The composition of claim 1, further comprising 0.2 to amount of Vanilla extract is 0.5% to 2.5%. 2% of capsaicin. 11. The composition of claim 1, further comprising an 23. A method of reducing the size of one or more tumors in effective amount of capsaicin. a mammal, the method comprising: 12. The composition of claim 11, wherein the effective administering to a mammal having a tumor a composition amount of capsaicin is 0.2 to 2%. containing an effective amount of curcumin, an effective 13. The composition of claim 1, further comprising phar amount of ginger extract and an effective amount of maceutically acceptable excipients. Vanilla extract. 14. The composition in claim 13, wherein the excipients are selected from a group consisting of granulating agents,